The objective is to elucidate the effects of influenza (flu) virus infection and flu vaccines on a natural host T cell regulatory mechanism involving expression of indoleamine 2,3 dioxygenase (IDO). IDO-mediated T cell suppression contributes to chronic inflammatory syndromes of clinical relevance, including tumor growth, autoimmune, allergic, and graft-versus-host diseases. IDO activity blocks T cell responses to fetal tissues during pregnancy, and IDO over-expression enhances transplant survival. Flu infection induces a dramatic increase in IDO activity in lungs, and IDO activity facilitates secondary infections such as pneumonia. We hypothesize that IDO attenuates effector T cell immune responses to flu infection and to preventative vaccines. Such effects may promote tissue healing, but may blunt T cell responses to flu infection, impede generation protective immunity, and increase the risk of secondary infections. IDO expression by some plasmacytoid dendritic cells (pDCs) inhibits T cell responses at sites of inflammation. In preliminary studies we show that chemically-induced skin inflammation induced pDCs in skin draining lymph nodes (dLNs) to express IDO. IDO+ pDCs acquired potent T cell regulatory functions that blocked T cell clonal expansion, and triggered regulatory T cells (Tregs) to acquire suppressor activity. In studies proposed, we will employ new mouse strains and viral vectors to ablate IDO in an established murine flu infection model, and assess the effects of IDO ablation on flu-specific immunity, memory generation, and infection kinetics. We will identify lung cells expressing IDO, and inflammatory signals that stimulate IDO (Aim 1). In parallel, we will elucidate the effects of lung IDO+ cells on flu-specific effector and memory T cells (Aim 2). Related studies will focus on the effects of IDO ablation on flu vaccine prophylaxis and efficacy (Aim 3), and a novel means to enhance therapeutic vaccination to combat flu infections (Aim 4). Completion of studies proposed will improve understanding of the role of IDO in regulating T cell responses to flu, and will create novel opportunities for improving therapeutic interventions protect against flu.